Angiogenesis is a physiological process involving activation of endothelial cells from a quiescent state to a migratory and proliferative phenotype in response to specific biological signals to form new blood vessels. It is an essential feature of growth and development, heart and kidney function and wound healing. Pathological angiogenesis is involved in a number of diseases such as cancer and inflammatory conditions such as rheumatoid arthritis and atherosclerosis. It plays a critical role in the growth and spread of cancer and is therefore a key target in cancer therapy.
New blood vessel formation entails proliferation of endothelial cells and remodelling of the extracellular matrix (ECM). Integrins, which play a major role in this response, exist in various activation states on the cell surface and modulate the migratory and adhesive characteristics of cells through interactions with the ECM. Other cell surface receptors also interact with ECM ligands leading to signalling cascades that can alter the activation state of integrins. Syndecans are an example of such molecules.
A number of inhibitors have been developed to suppress angiogenesis. For example, small molecules such as sorafenib and pazopanib inhibit kinases that promote angiogenesis; bevacizumab targets vascular endothelial growth factor (VEGF), a potent pro-angiogenic signalling molecule. There are however a number of serious side effects commonly associated with the use of anti-angiogenic compounds for example haemorrhage, hypertension, lymphopenia and diarrhea. In addition in the case of VEGF targeting therapies there is also a significant number of patient non-responders (˜45%).
Thus there is a need for alternative therapies and methods for treating diseases associated with angiogenesis.
Syndecans are a family of transmembrane receptors with roles in cell adhesion, migration and growth factor signalling. Each syndecan molecule comprises a short highly conserved cytoplasmic domain, a transmembrane domain and a larger extracellular domain (ectodomain). In mammals, there are four syndecan family members—syndecans-1, -2, -3 and -4. In common with the other family members syndecan-2 has a short cytoplasmic domain, a single pass transmembrane domain and a larger extracellular domain which is substituted toward the N-terminus with heparan sulphate (HS) side chains and can be shed from the cell surface. Syndecan shedding is a feature of many cell types and occurs in response to stimuli such as inflammatory mediators and growth factors. Syndecan-2 and CD148 are molecules intimately associated with the vasculature. Syndecan-2 is expressed on fibroblasts, leukocytes and ECs and studies in zebrafish reveal syndecan-2 to be essential for branching angiogenesis.
A number of research groups have shown that syndecan-2 plays an important role in angiogenesis. For example, Chen et al (Blood; 103 (5); 1710-9; 2004); have shown that syndecan-2 is essential for angiogenic sprouting in zebrafish. Noguer et al (Experimental Cell Research, Vol 315: 5, 795-808, March 2009) have demonstrated that downregulation of syndecan-2 impairs angiogenesis in human microvascular endothelial cells.
The inventors have surprisingly found that a portion of the syndecan-2 molecule has an unexpected anti-angiogenic effect.